Inhibition of histone deacetylases induces formation of multipolar spindles and subsequent p53-dependent apoptosis in nasopharyngeal carcinoma cells
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Min Yan1,2,*, Yuan-min Qian1,*, Cai-feng Yue1,3, Zi-feng Wang1, Bi-cheng Wang1, Wei Zhang1, Fei-meng Zheng1,4, Quentin Liu1
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Institute of Cancer Stem Cell, Dalian, China
2Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
3Department of Laboratory Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
4Department of Medical Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
*These authors have contributed equally to this work
Quentin Liu, email: [email protected]
Keywords: histone deacetylases, p53, spindle, apoptosis, Nutlin-3
Received: February 25, 2016 Accepted: May 16, 2016 Published: June 8, 2016
Histone deacetylases (HDACs) play crucial roles in the initiation and progression of cancer, offering a promising target for cancer therapy. HDACs inhibitor MGCD0103 (MGCD) exhibits effective anti-tumor activity by blocking proliferation and inducing cell death in malignant cells. However, the molecular mechanisms of HDACs inhibition induces cell death have not been well elucidated. In this study, we showed that MGCD effectively restored histone acetylation, suppressed cell growth and induced apoptosis in two-dimensional (2D) and three-dimensional (3D) cultured CNE1 and CNE2 nasopharyngeal carcinoma (NPC) cells. Importantly, MGCD arrested cell cycle at mitosis (M) phase with formation of multipolar spindles, which was associated with activated p53-mediated postmitotic checkpoint pathway to induce apoptotic cell death. Moreover, MGCD-induced apoptosis was decreased by inhibition of p53 using short interfering RNA (siRNA), suggesting that p53 was required for MGCD-induced cell apoptosis. Consistently, MGCD in combination with Nutlin-3, a MDM2 inhibitor showed synergistic effect on inducing apoptosis in 2D and 3D cultured CNE2 cells. Collectively, our data revealed that MGCD induced p53-dependent cell apoptosis following formation of multipolar spindles in NPC cells, suggesting the therapeutic potential of combinations of HDACs and MDM2 inhibitors for NPC treatment.
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